Investigation of cerebellar involvement in AUD

AUD 中小脑受累的调查

• 批准号: 10502668
• 负责人: JOHN E DESMOND
• 金额: $ 59.87万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502668
• 关键词: Address; Alcoholism; Alcohols; Animals; Anodes; Behavioral; Blinking; Brain; Brain Stem; Brain region; Cathodes; Cell Nucleus; Cerebellar Diseases; Cerebellum; Corpus striatum structure; Coupling; Data; Disinhibition; Event; Functional Magnetic Resonance Imaging; Functional disorder; Human; Individual; Intervention; Investigation; Lead; Link; Measures; Motor Cortex; Nature; Neurons; Nucleus Accumbens; Outcome; Output; Participant; Pathway interactions; Patients; Performance; Prosencephalon; Psychophysiology; Reflex action; Relapse; Rest; Rewards; Signal Transduction; Source; Stimulus; Structure; System; Therapeutic; Ventral Tegmental Area; addiction; alcohol craving; alcohol cue; alcohol effect; alcohol response; alcohol use disorder; base; classical conditioning; conditioned place preference; conditioning; craving; cue reactivity; disorder control; drinking; expectation; eyeblink conditioning; financial incentive; hemodynamics; motor control; neuroregulation; neurotransmission; response; reward processing

Recent animal studies have provided new evidence that the cerebellum may have a stronger link to the reward system of the brain than was previously recognized. Direct projections from cerebellar deep nuclei (DN) to the ventral tegmental area (VTA) have been identified, and stimulation of these cerebellar afferents to the VTA was found to be rewarding. Such findings raise the possibility that cerebellar dysfunction could contribute substantially to addiction via a cerebellar influence over VTA. Consistent with animal findings, we have found in human fMRI preliminary data strong cerebellar and VTA activation in response to alcohol cues relative to non- alcohol stimuli in patients with alcohol use disorder (AUD) compared to controls, and close coupling observed between DN and VTA activation. Studying AUD and control participants, this project will address three important questions. The first is: What is the nature of cerebellar input to the VTA, and how is it perturbed in AUD? A number of investigations have suggested that when a stimulus is presented, the cerebellum generates a prediction of events that will follow based on prior associative learning, and then compares predicted and actual outcomes to generate a prediction error. We hypothesize that these functions are disrupted in AUD. Our preliminary data show that when an expected stimulus does not occur, a strong prediction error signal in the form of increased functional connectivity (FC) between cerebellum and its projection target is observed, and we found an analogous increase in DN-VTA FC, that was abnormal in AUD patients, when alcohol pictures were presented. In Aim 1, using fMRI and a monetary incentive task, we will investigate if DN-VTA FC reflects reward prediction and/or positive or negative reward prediction error. The second question is: Is the amount of activation in brain reward centers that is elicited by alcohol stimuli related to the amount of dysfunction in the cerebellum? In Aim 2 we will investigate 2 measures of cerebellar integrity to determine their relationship with the magnitude of alcohol cue related activation in cerebellar, VTA, and other reward structures, and with DN- VTA FC: (1) The timing of the undershoot of the cerebellar hemodynamic response function (HRF), which has been found to be correlated with number of lifetime drinks; and (2) classical eyeblink conditioning, for which the cerebellum is necessary. The third question is: Can abnormal cerebellar activation and FC, as well as alcohol craving, be reduced by non-invasive cerebellar stimulation? In Aim 3, Using fMRI combined with cerebellar transcranial direct current stimulation (tDCS) during a cue reactivity task, we hypothesize that in AUD participants cerebellar and VTA activation will be reduced, DN-VTA FC will be normalized, and alcohol craving will be reduced. We will examine, using both resting state fMRI and psychophysiological interaction analysis, the effects of tDCS on FC among important structures of the reward system as well as on DN-VTA FC. These investigations will lead to a better understanding of the involvement of the cerebellum in AUD, as well as the therapeutic potential of cerebellar modulation.

最近的动物研究提供了新的证据，表明小脑可能与奖励有更强的联系 大脑的系统比以前认识的要多。从小脑深核（DN）到大脑的直接投影 腹侧被盖区（VTA）已被确定，这些小脑传入神经对 VTA 的刺激是 发现是有益的。这些发现提出了小脑功能障碍可能导致的可能性 很大程度上是通过小脑对 VTA 的影响而导致成瘾。与动物研究结果一致，我们发现 人类功能磁共振成像初步数据显示，相对于非酒精信号，小脑和腹侧被盖区对酒精信号的激活更强。 与对照组相比，酒精使用障碍 (AUD) 患者的酒精刺激，并观察到紧密耦合 DN 和 VTA 激活之间。通过研究 AUD 和控制参与者，该项目将解决三个问题 重要的问题。第一个是：小脑对 VTA 的输入的性质是什么，以及它是如何受到干扰的。 澳元？许多研究表明，当刺激出现时，小脑会产生 根据先前的联想学习对接下来发生的事件进行预测，然后将预测的事件与预测的事件进行比较 实际结果会产生预测误差。我们假设这些功能在澳元中被破坏。我们的 初步数据表明，当预期的刺激没有发生时，系统中会出现强烈的预测误差信号。 观察到小脑与其投射目标之间功能连接（FC）增加的形式，并且 我们发现当酒精图片时 DN-VTA FC 也有类似的增加，这在 AUD 患者中是异常的 被提出。在目标 1 中，使用 fMRI 和货币激励任务，我们将调查 DN-VTA FC 是否反映 奖励预测和/或正或负奖励预测错误。第二个问题是：金额是多少？ 酒精刺激引起的大脑奖励中心的激活与大脑功能障碍的程度有关 小脑？在目标 2 中，我们将研究小脑完整性的 2 种测量方法，以确定它们与 小脑、VTA 和其他奖赏结构中酒精线索相关激活的程度，以及 DN- VTA FC：（1）小脑血流动力学反应函数（HRF）下冲的时间，其具有 被发现与终生饮酒次数相关； (2) 经典的眨眼条件反射，其中 小脑是必要的。第三个问题是：小脑激活和FC会异常吗，还有酒精 通过非侵入性小脑刺激来减少渴望？目标 3，使用 fMRI 结合小脑 在提示反应性任务期间进行经颅直流电刺激（tDCS），我们假设在 AUD 参与者小脑和 VTA 激活将减少，DN-VTA FC 将正常化，并且对酒精的渴望 将会减少。我们将使用静息态功能磁共振成像和心理生理学相互作用分析来检查， tDCS 对奖励系统重要结构中的 FC 以及 DN-VTA FC 的影响。这些 研究将有助于更好地了解小脑在 AUD 中的参与，以及 小脑调节的治疗潜力。